PLEKHM1 is located at chromosome 17q21.31, has 12 exons, 1056 amino acids. It encodes a protein that is required in the late endosomal/lysosomal vesicles and bone resorption. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive osteopetrosis 6 (MIM#611497 ) and autosomal dominant osteopetrosis 3 (MIM#618107). This is a curation of autosomal recessive osteopetrosis 6 (MONDO:0012679). PLEKHM1 was first reported in relation to autosomal recessive osteopetrosis 6 in 2007 (Van Wesenbeeck et al., 2007 PMID: 17404618).
One variant (canonical splice-site) reported in one publication has been included in this curation (PMID: 17404618). An additional case harboring 2 heterozygous PLEKHM1 mutations in exon 4 and exon 7 was published, although segregation data and the nature of the variants was not revealed (PMID: 28290981). The mechanism of pathogenicity is loss-of-function. A total of 3.0 genetic points was reached. This gene-disease relationship is also supported by biochemical, and mouse and rat models (PMID: 17404618, 27777970, 2122370).
In summary, there is Moderate evidence supporting the relationship between PLEKHM1 and autosomal recessive osteopetrosis 6. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date (03/06/24) (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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